NPHS2 variation in focal and segmental glomerulosclerosis Public Deposited

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Creator
  • Appel, Gerald B
    • Other Affiliation: Glomerular Disease Center, Columbia University College of Physicians and Surgeons, New York, NY, USA
  • Falk, Ronald J.
    • Affiliation: School of Medicine, Department of Medicine, Division of Nephrology and Hypertension, UNC Kidney Center
  • Katz, Avi
    • Other Affiliation: Department of Pediatrics, University of Alabama, Birmingham, Alabama, USA
  • Uscinski, Andrea
    • Other Affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
  • Pollak, Martin R
    • Other Affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
  • Zhang, Kang
    • Other Affiliation: Johan A. Moran Eye Center and Department of Ophthalmology & Visual Science, University of Utah, Salt Lake City, USA
  • Curhan, Gary C
    • Other Affiliation: Renal Division, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
  • Savige, Judy
    • Other Affiliation: Department of Medicine, The Northern Hospital, Epping, Victoria, Australia
  • Needham, Alexander
    • Other Affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
  • Polu, Krishna
    • Other Affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
  • Tonna, Stephen J
    • Other Affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
  • Harmon, Jennifer
    • Other Affiliation: Johan A. Moran Eye Center and Department of Ophthalmology & Visual Science, University of Utah, Salt Lake City, USA
  • Kaplan, Bernard S
    • Other Affiliation: Department of Pediatrics, Division of Nephrology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
  • Al-Waheeb, Salah
    • Other Affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
  • Jerums, George
    • Other Affiliation: Endocrine Centre and Department of Medicine, Heidelberg Repatriation Hospital, Victoria, Australia
Abstract
  • Abstract Background Focal and segmental glomerulosclerosis (FSGS) is the most common histologic pattern of renal injury seen in adults with idiopathic proteinuria. Homozygous or compound heterozygous mutations in the podocin gene NPHS2 are found in 10–30% of pediatric cases of steroid resistant nephrosis and/or FSGS. Methods We studied the spectrum of genetic variation in 371 individuals with predominantly late onset FSGS (mean age of onset 25 years) by analysis of DNA samples. Results We identified 15 non-synonymous alleles that changed the amino acid sequence in 63 of the subjects screened (17%). Eight of these (p.R138Q, p.V180M, p.R229Q, p.E237Q, p.A242V, p.A284V, p.L327F and the frameshift 855–856 delAA) are alleles previously reported to cause FSGS in either the homozygous or compound heterozygous states, while the remaining 7 (p.R10T, p.V127W, p.Q215X, p.T232I, p.L270F, p.L312V and the frameshift 397delA) are novel alleles that have not been demonstrated previously. Twelve individuals of the 371 (3.2%) screened had two likely disease-causing NPHS2 alleles, present in either a homozygous or compound heterozygous state. We genotyped the two most common of the non-synonymous NPHS2 alleles (p.A242V and p.R229Q) identified by resequencing in participants from the Nurses' Health Study and also genotyped p.R229Q in 3 diabetic cohorts. We found that the presence of either of these variants does not significantly alter the risk of albuminuria in the Nurses' Health participants, nor does p.R229Q associate with "diabetic nephropathy". Conclusion NPHS2 mutations are a rare cause of FSGS in adults. The most common non-synonymous NPHS2 variants, p.R229Q and p.A242V, do not appear to alter the risk of proteinuria in the general population nor does p.R229Q associate with measures of kidney dysfunction in diabetic individuals. Our results help clarify the frequency of FSGS-causing NPHS2 mutations in adults and broaden our understanding of the spectrum of NPHS2 mutations that lead to human disease.
Date of publication
Identifier
  • 18823551
  • doi:10.1186/1471-2369-9-13
Resource type
  • Article
Rights statement
  • In Copyright
Rights holder
  • Stephen J Tonna et al.; licensee BioMed Central Ltd.
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Journal title
  • BMC Nephrology
Journal volume
  • 9
Journal issue
  • 1
Page start
  • 13
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1471-2369
Bibliographic citation
  • BMC Nephrology. 2008 Sep 29;9(1):13
Access
  • Open Access
Publisher
  • BioMed Central Ltd
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